Inhibitory effects of dronedarone on muscarinic K+ current in guinea pig atrial cells

Dronedarone (SR33589), an amiodarone-like noniodinated antiarrhythmic agent, is undergoing clinical trials in atrial fibrillation. Because vagal activation plays a role in the pathophysiology of supraventricular arrhythmias, we have assessed the ability of dronedarone (0.01, 0.1, and 1 muM), compared with amiodarone (0.1, 1, and 10 muM) to inhibit the muscarinic acetylcholine receptor-operated K+ current (I-K(ACh)) in single cells isolated from guinea pig atria (patch-clamp technique). I-K(ACh) was activated by extracellular application of carbachol (10 muM) or by intracellular loading with GTP-gamma -S (100 muM). Dronedarone and amiodarone reduced the carbachol-induced I-K(ACh) with an IC50 (concentration required for 50% inhibition) slightly above 10 nM and 1 muM, respectively. Dronedarone also inhibited the GTP-gamma -S induced K+ current by 28% and 58% at 0.01 and 0.1 muM, respectively. These data suggest that dronedarone inhibits I-K(ACh) by depressing the function of K-ACh channel itself or associated GTP-binding proteins. Compared with amiodarone, dronedarone is approximately 100 times more potent on I-K(ACh) and seems more selective in inhibiting I-K(ACh) with respect to its antagonism of other inward and outward currents reported in the literature. This relative high potency of dronedarone to reduce I-K(ACh) may be involved, at least in part, in the antiarrhythmic action of dronedarone against atrial fibrillation.